The burgeoning family of chemo-attractant cytokines, also known as chemokines, comprises the most diverse and largest subset of cytokines identified to date. Chemokines are characterized by their capacity to induce the directional migration and activation of leukocytes, as well as other somatic cell types, and thus play major roles in acute and chronic inflammation (William, P. et al., Fundamental Immunology, 4th Edition, Lippincott-Raven pp. 791-794 (1990)).
Chemokines also promote humoral and cell-mediated immune reactions; regulate cell adhesion, angiogenesis, leukocyte trafficking, and homing; and contribute to lymphopoiesis and hematopoiesis. Chemokines are produced by a wide variety of leukocytes and other cell types in response to irritants, polyclonal stimulants, antigens, and endogenous cytokines. A variety of chemokines have been detected at local inflammatory sites in a great number of disease states. Chemokines play a central role in host defense against infectious organisms, including HIV-1. Furthermore, chemokines participate in the pathogenesis of diverse conditions such as reperfusion injuries including strokes, acute respiratory distress syndrome (ARDS), immune complex-induced glomerulonephritis, atherosclerosis, and autoimmune reactions (William, P. et al., Fundamental Immunology, 4th Edition, Lippincott-Raven pp. 791-794 (1990)).
IP-10 (CXCL10) is a chemokine that is induced by interferon γ and is the ligand for CXCR3. CXCR3 is expressed on human activated/memory T cells (Qin et al., J. Clin. Invest. 101:746 (1998)). Over-expression of IP-10 at the site of inflammation potently attracts CDCR3+ activated T cells and antibody secreting plasma cells. In human patient samples, elevated levels of IP-10 have been found in a number of autoimmune diseases, including multiple sclerosis (MS) (Balashov et al., Proc. Natl. Acad. Sci USA 96:6873 (1999)); Sorensen et al., J. Neuroimmunol. 127:59 (2002)), rheumatoid arthritis (RA) (Patel et al., Clin. Immunol 98:39 (2001)), systemic lupus erythematosis (Narumi et al., Euro. J. Immunol. 32:1784 (2002)), Type-I diabetes (Nicolette et al., Dialectologies 45:1107 (2002)), Graves' disease (Romagnani et al., Am. J. Patrol. 161:195 (2002)), psoriasis (Flier, 2002; Gottlieb et al., J. Exp. Med. 168:941 (1998)), and autoimmune liver disease (Nishioji et al, Clin. Exp. Immunol. 123:271 (2001)). Animal model studies have also demonstrated that IP-10 may play a role in multiple sclerosis (MS), rheumatoid arthritis (RA), and airway hyperactivity and inflammation. U.S. Pat. No. 6,184,358 discloses the antibodies to and nucleic acids encoding CXCR3 (this and all other U.S. patents and patent applications cited herein are hereby incorporated herein in their entirety). PCT Publication No. WO 02/15932 is directed to a method of preventing demyelination in a subject by administering to a subject a neutralizing agent specific for IP-10.
There have been reports that elevated IP-10 levels have been detected in human IBD. Grimm, M., et al. reported detecting elevated IP-10 levels in formalin-fixed colon resections from Crohn's disease (hereinafter, “CD”) patients as compared to colon resections from non-inflamed (but cancer bearing) colons by in situ hybridization (Inflammatory Bowel Dis. 2:88-96 (1996)). Uguccioni, M., et al. reported detecting elevated IP-10 expression in endoscopic biopsies from ulcerative colitis (hereinafter, “UC”) patients as compared to biopsies from normal colons by immunohistochemistry (Amer. J. Pathol. 155:331-6 (1999)). However, the above-referenced publications have not examined the therapeutic potential of anti-IP-10 antibodies in inflammatory bowel diseases (hereinafter, “IBD”). As IP-10 is induced by both IFN-γ and TNF-α, an antibody targeting this chemokine would be expected to operate downstream of both of these cytokines in the inflammatory pathway, and thus could be a more specific intervention and exhibit fewer or less severe side effects, as compared with the existing approaches for treating IBD. The present invention provides for potent neutralizing anti-IP-10 antibodies comprising the disclosed amino acid sequences and the methods of using an antagonist of IP-10 for the treatment of IBD, including CD and UC.